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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Hypoxia-Ischemia and Brain infarction

and .

Correspondence to Laura L. Dugan, Washington University, Department of Neurology, 660 South Euclid Avenue, St. Louis, Missouri 63110.

Hypoxic-ischemic brain injury continues to be the third leading cause of death in the United States, affecting over half a million new victims each year. Of these, nearly one-third will die and another third will be left with severe and permanent disability. Unlike ischemic injury to many other tissues, the severity of disability is not predicted well by the amount of brain tissue lost. For example, damage to a small area in the medial temporal lobe may lead to severe disability, such as loss of speech, while damage to a greater volume elsewhere has little effect on function. The degree of disability does not simply reflect the severity or distribution of impaired blood supply. Populations of cells lying side by side in the brain can display dramatically different vulnerabilities to equivalent degrees of ischemia. Although a great deal has been learned about how nervous system anatomy, physiology and biochemistry interact to modify hypoxic-ischemic brain injury, much remains to be learned about what features contribute to the special vulnerability of the brain to stroke and of specific cell populations to hypoxic-ischemic injury during stroke.

Energy failure, an early consequence of hypoxia-ischemia, causes disruption of ionic homeostasis and accumulation of extracellular neurotransmitters

As discussed in Chapter 31, normal energy metabolism in the brain has several unusual features, including a high metabolic rate, limited intrinsic energy stores and critical dependence on aerobic metabolism of glucose. Reflecting this special metabolic status, as well as the existence of several unique injury mechanisms discussed below, the brain exhibits higher vulnerability to ischemic injury than most other tissues. Ischemic brain injury occurs in several clinical settings. The most common is stroke, focal disruption of blood supply to a part of the brain. Other settings include transient impairment of blood flow to the entire brain, global ischemia, as occurs during cardiac arrest.

When brain hypoxia or ischemia occurs, tissue energy demands cannot be met, so ATP levels fall. Loss of ATP results in decreased function of active ion pumps, such as the Na,KATPase, the most important transporter for maintaining high intracellular concentrations of K+ (~155 mM) and low intracellular concentrations of Na+ (~12 mM) (see Chap. 5). Loss of ion pump function allows rundown of transmembrane ion gradients (Fig. 34-1), leading to membrane depolarization, the opening of voltage-sensitive ion channels and a cascade of subsequent events, which, if sustained, lead ultimately to cell death. Depending on the circumstances, this death may be restricted to selectively vulnerable neuronal populations or may involve all cells, termed tissue infarction.

Figure 34-1. Changes in extracellular ion concentrations following ischemia.

Figure 34-1

Changes in extracellular ion concentrations following ischemia. Extracellular pH begins to decrease immediately after the onset of ischemia. This change is accompanied by slight increases in the extracellular concentrations of K+, Cl and Na+ (more...)

Within seconds of an ischemic insult, normal brain electrical activity ceases due to the activation of membrane K+ channels and widespread neuronal hyperpolarization [1]. The hyperpolarization may be due to opening of K+ channels responding to acute changes in local concentrations of ATP, H+ or Ca2+, or it may reflect altered nonheme metalloprotein association with and regulation of specific K+ channels [2]. This response, presumably protective, however fails to preserve high-energy phosphate levels in tissue as concentrations of phosphocreatine (PCr) and ATP fall within minutes after ischemia onset [3]. The fall in pO2 during ischemia leads to enhanced lactic acid production as cells undergo a Pasteur shift from a dependence on aerobic metabolism to a dependence on glycolysis. The resulting lactic acidosis decreases the pH of the ischemic tissue from the normal 7.3 to intra-ischemic values ranging from 6.8 to 6.2, depending, in part, on the preischemic quantities of glucose available for conversion to lactic acid. In addition, efflux of K+ from depolarizing neurons results in prolonged elevations in extracellular [K+] (Fig. 34-1) and massive cellular depolarization, a state known as spreading depression, which can propagate in brain tissue. Rapid inactivation of O2-sensitive K+ channels by decreased pO2 may represent one mechanism whereby neurons put a brake on this ongoing K+ efflux [2]. Other cellular ion gradients are also lost; thus, intracellular Na+ and Ca2+ rise (Fig. 34-2) and intracellular Mg2+ falls.

Figure 34-2. Changes in intracellular and extracellular Ca2+ during ischemia-reperfusion and the effects of the N-methyl-d-aspartate receptor antagonist MK-801.

Figure 34-2

Changes in intracellular and extracellular Ca2+ during ischemia-reperfusion and the effects of the N-methyl-d-aspartate receptor antagonist MK-801. Intracellular Ca2+, circles; extracellular Ca2+, squares; with MK-801, dark orange; without MK-801, light (more...)

Extracellular concentrations of many neurotransmitters are increased during hypoxia-ischemia. Depolarization-induced entry of Ca2+ via voltage-sensitive Ca2+ channels stimulates release of vesicular neurotransmitter pools, including the excitatory amino acid neurotransmitter glutamate. At the same time, Na+-dependent uptake of certain neurotransmitters, including glutamate, is impaired (Chap. 5). High-capacity uptake of glutamate by the glutamate transporter couples the uptake of one glutamate and two Na+ with the export of one K+ and one HCO3 (or OH) (see Fig. 15-7). When the cellular ion gradients are discharged, the driving force for glutamate uptake is lost. In addition, glutamate uptake by the widely expressed astrocyte high-affinity glutamate transporter GLT-1, or excitatory amino acid transporter-2 (EAAT2), and the neuronal transporter, or EAAT3, can be downregulated by free radical-mediated oxidation of a redox site on the transporter [4]. Furthermore, since the transporter is electrogenic, that is, normally transferring a positive charge inward, membrane depolarization can lead to reversal of the transporter, producing glutamate efflux [5]. Thus, both impaired glutamate uptake and enhanced glutamate release contribute to sustained elevations of extracellular glutamate in the ischemic brain. Microdialysis of ischemic rat brain has detected an increase from the resting extracellular glutamate concentrations of 1 to 2 μM up to concentrations in the high micromolar or even low millimolar range.

Focal and global ischemia produce different distributions of injury

Ischemic injury to the brain can result from several different processes. Focal ischemia, which accounts for a majority of strokes, occurs when an artery supplying a region of the brain is occluded, either by an embolus, which is generally material broken off from a plaque in a large artery or a thrombus in the heart, or by a thrombus or platelet plug which forms directly in the affected artery (Fig. 34-3AC). While focal ischemic insults generally reflect the distribution of vascular supply to a region, the area of infarction is typically less than the entire distribution of the occluded artery due to the presence of collateral circulation at the borders of the region supplied by the occluded vessel. The ultimate area of infarction will depend on the duration and degree of vascular occlusion and the availability of collateral blood supply [6]. The region of the brain supplied uniquely by the occluded artery develops the most severe injury, termed the ischemic core, while the rim of tissue surrounding the core, termed the penumbra, which has the benefit of some maintained blood flow supplied by collateral circulation, sustains less severe injury. Focal ischemia may also accompany other acute brain insults, such as intracerebral hemorrhage or trauma.

Figure 34-3. Focal ischemia produces a core of infarction caused by occlusion of the vessel supplying the affected brain tissue.

Figure 34-3

Focal ischemia produces a core of infarction caused by occlusion of the vessel supplying the affected brain tissue. A 53-year-old man presented with imbalance, various cranial neuropathies and hiccups. A: Angiography revealed high-grade stenosis and clot (more...)

Reversible global ischemia, such as occurs during cardiac arrest and resuscitation, reflects a transient loss of blood flow to the entire brain and generally results in the death of certain selectively vulnerable neuronal populations. Hypoxia accompanies ischemic insults but may also occur without loss of blood flow, for example, during near drowning or carbon monoxide poisoning. Hypoglycemia produces brain injury that has several features in common with ischemic injury. Neurons are more susceptible than glial cells to ischemia, hypoxia or hypoglycemia; and the phylogenetically newer regions of the brain, including the cortex and cerebellum, are affected to a greater extent than the brainstem [6].

“Selective vulnerability” of certain neurons is not explained by vascular distribution

As recognized by Vogt and Vogt (see in [6]), the juxtaposition of relatively vulnerable and relatively resistant neuronal populations within a single vascular distribution suggests that intrinsic tissue factors contribute heavily to ischemic neuronal vulnerability. For example, pyramidal neurons in the CA1 subfield of the hippocampus die after 5 to 10 min of global ischemia, while neurons in the nearby CA3 region are preserved. Populations of neurons that are selectively vulnerable to ischemia include cortical pyramidal neurons, cerebellar Purkinje cells, hippocampal CA1 pyramidal neurons and subpopulations in the amygdala, striatum, thalamus and brainstem nuclei (Fig. 34-4). Some of the mechanisms that may contribute to selective vulnerability of certain cell populations to ischemic injury are discussed further below.

Figure 34-4. Rat hippocampus showing neuronal populations that are selectively vulnerable to ischemic damage.

Figure 34-4

Rat hippocampus showing neuronal populations that are selectively vulnerable to ischemic damage. A: control; B: ischemia. A brief period of global ischemia causes nearly complete loss of neurons in the CA1 region (arrows) of the hippocampus, while neurons (more...)

Image ch15f7

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28046

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